The major goal of this proposal is to build on our several recent unexpected findings to understand how extracellular calcium regulates the basal excitability of neurons. Under pathophysiological conditions such as hypocalcemia and epilepsy, concentration of extracellular calcium can drop significantly in the brain. Extracellular calcium concentration can also change under physiological conditions in brain regions with high neuronal density and in microdomains such as the synaptic cleft. A decrease in extracellular calcium concentration usually excites neurons. The molecular mechanisms underlying the control by extracellular calcium are poorly understood, in contrast with the extensively investigated intracellular roles of calcium as a second messenger. We propose that a major mechanism by which extracellular calcium regulates excitability is through the NALCN cation channel we discovered. Using biochemical, electrophysiology and mouse genetics approaches, we will 1) determine the relative contribution of NALCN to the neuronal excitation by extracellular calcium in several brain regions; 2) define the structural requirements of the protein in the calcium sensitivity; and 3) uncover the signals that regulate the channel complex. Results from these studies will help us understand how body calcium regulates neuronal excitability at the molecular level under physiological and pathophysiological conditions such as paralysis, seizure and epilepsy.